1. Field of Invention
The current invention relates to clinical diagnostic systems and methods, and more particularly to point-of-care mass spectrometer systems and methods.
2. Discussion of Related Art
Proteins synthesized in the nucleus of cells are degraded into small peptides by proteasomes as part of the natural turnover process. In the class I system these (generally nine amino acid) peptides are passed into the endoplasmic reticulum via the TAP transporter channel and combined with the multiple histocompatability (MHC) molecule, forming a complex that is transported to the cell surface and displayed to the immune system. Both the MHC and antigen are recognized by killer T cells or cytotoxic T lymphocytes (CTLs) and is known as restricted recognition (see FIG. 1). Failure to recognize either the MHC molecule or the antigen as self molecules produces a complex immunological response that results in cell lysis and cell death. Non-self MHC molecules may occur as a result of the presence of non-self cells (as is the case in organ or tissue transplantation) and, in essence, results in rejection. Non-self peptides are those that are synthesized in the nucleus of the cell as a result of viral or retroviral infection, or from altered cells, such as those produced in cancer. In this case the immune response is to rid the body of infected or altered cells. In some rarer cases, CTLs react to the presence of self peptides, producing an autoimmune disease. Beginning with the pioneering work of Hunt et al. (see Hunt, D. F.; Henderson, R. A.; Shabanowitz, J.; Sakaguchi, K.; Michel, H.; Sevilir, N.; Cox, A. L.; Appella, E.; Englehard, V. H., Characterization of Peptides Bound to the Class I MHC Molecule HLA-A2.1 by Mass Spectrometry, Science 255 (1992) 1261-1263; Henderson, R. A.; Michel, H.; Sakaguchi, K.; Shabanowitz, J.; Appella, E.; Hunt, D. F.; Englehard, V. H., HLA-A2.1-Associated Peptides from a Mutant Cell Line: a Second Pathway of Antigen Presentation, Science 255 (1992) 1264-1266; Hunt, D. F.; Michel, H.; Dickenson, T. A.; Shabanowitz, J.; Cox, A. L.; Sakaguchi, K.; Appella, E. Grey, H. M.; Settee, A., Peptides Presented to the Immune System by the Murine Class II Major Histocompatability Complex Molecule I-Ad, Science 256 (1992) 1817-1820; Henderson, R. A.; Cox, A. L.; Sakaguchi, K.; Appella, E.; Shabanaowitz, J.; Hunt, D. F.; Engelhard, V. H., Direct Identification of an Endogenous Peptide Recognized by Multiple HLA-A2.1-Specific Cytotoxic T Cells, Proc. Natl. Acad. Sci. USA 90 (1993) 10275-10279, the entire contents of which are incorporated herein by reference), mass spectrometry has been used for a number of years for the structural characterization or amino acid sequencing of both class I (viral) and class II (bacterial) antigens.
Most of these research studies have utilized electrospray ionization (ESI) because of the ability to directly couple high performance liquid chromatography (HPLC) fractionation with the mass spectrometer. However, there remains a need for mass spectrometer systems and methods that are portable and/or can be used at the point of care.
Patents related to MHC class I antigens include U.S. Pat. No. 6,660,276; U.S. Pat. No. 6,558,671; U.S. Pat. No. 6,521,598; U.S. Pat. No. 6,315,905; U.S. Pat. No. 6,139,734; U.S. Pat. No. 5,770,201; U.S. Pat. No. 6,537,560; U.S. Pat. No. 6,270,778; U.S. Pat. No. 5,994,523; U.S. Pat. No. 5,874,560; U.S. Pat. No. 5,844,075; U.S. Pat. No. 5,809,475; and U.S. Pat. No. 5,830,641 each of which is incorporated herein by reference.
Patents related to mass spectrometers include U.S. Pat. No. 5,101,105, Neutralization/chemical reionization tandem mass spectrometry method and apparatus therefore, Fenselau, C.; Cotter, R. J., Mar. 31, 1992; U.S. Pat. No. 5,202,563, Tandem time-of-flight mass spectrometer, Cotter, R. J.; Cornish, T. J., Apr. 13, 1993; U.S. Pat. No. 5,399,857, Method and apparatus for trapping ions by increasing trapping voltage during ion introduction, Doroshenko, V. M; Cotter, R. J., Mar. 21, 1995; U.S. Pat. No. 5,464,985, Non-linear reflectron, Cornish, T. J.; Cotter, R. J., Nov. 7, 1995; U.S. Pat. No. 5,572,025, Method and apparatus for scanning an ion trap mass spectrometer in the resonance ejection mode, Cotter, R. J.; Doroshenko, V. M., Nov. 5, 1996; U.S. Pat. No. 5,696,376, Method and apparatus for isolating ions in an ion trap with increased resolving power, Doroshenko, V. M.; Cotter, R. J., Dec. 9, 1997; U.S. Pat. No. 5,814,813, Endcap reflectron for a time-of-flight mass spectrometer and method of using the same, Cotter, R. J.; Cornish, T. J., Sep. 29, 1998; U.S. Pat. No. 6,365,892, Method and apparatus for correction of initial ion velocity in a reflectron time-of-flight mass spectrometer, Cotter, R. J.; Doroshenko, V. M., Apr. 2, 2002, U.S. Pat. No. 6,518,568, Method and apparatus of mass-correlated pulsed extraction for a time-of-flight mass spectrometer, Kovtoun, V.; Cotter, R. J., Feb. 11, 2003, DM4042 (WO 2004/040612) Combined chemical/biological agent mass spectrometer detector, Cotter, R. J; DM4046 (WO 03/086589) Miniaturized sample-scanning mass spectrometer, Cotter, R. J; DM4077 (WO 03/107387) Non-linear time-of-flight mass spectrometer, Cotter, R. J.; Gardner, B. D; DM4080 (WO 03/103008) Time-of-flight mass spectrometer combining fields non-linear in time and space, Cotter, R. J.; Gardner, B. D.; Holland, J. D; DM4195, Tandem time-of-flight mass spectrometry, Cotter, R. J.; Iltchenko, S.; Gardner, B.; English, R. D.; DM4112 (WO 2004/013602); Combined Chemical/Biological Agent Detection by Mass Spectrometry, Bryden, W.; Cotter, R. J.; Eicelberger, S. each of which is incorporated herein by reference.